EP0769498B1 - Dérivés sulfonamide ayant une activité inhibitrice vis-à-vis de l'élastase humaine - Google Patents

Dérivés sulfonamide ayant une activité inhibitrice vis-à-vis de l'élastase humaine Download PDF

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Publication number
EP0769498B1
EP0769498B1 EP96307048A EP96307048A EP0769498B1 EP 0769498 B1 EP0769498 B1 EP 0769498B1 EP 96307048 A EP96307048 A EP 96307048A EP 96307048 A EP96307048 A EP 96307048A EP 0769498 B1 EP0769498 B1 EP 0769498B1
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Prior art keywords
phenyl
pyrrolidin
acid ester
butanoic acid
methylphenyl
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EP96307048A
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German (de)
English (en)
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EP0769498B9 (fr
EP0769498A1 (fr
Inventor
Takahiko C/O Minase Research Institute Nakae
Masashi c/o Minase Research Institute Kato
Takehito c/o Minase Research Institute Fujita
Kazuhito c/o Minase Research Institute Kawabata
Hiroyuki C/O Minase Research Institute Ohno
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Ono Pharmaceutical Co Ltd
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Ono Pharmaceutical Co Ltd
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Priority claimed from JP7272058A external-priority patent/JPH09165365A/ja
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    • C07D295/00—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms
    • C07D295/22—Heterocyclic compounds containing polymethylene-imine rings with at least five ring members, 3-azabicyclo [3.2.2] nonane, piperazine, morpholine or thiomorpholine rings, having only hydrogen atoms directly attached to the ring carbon atoms with hetero atoms directly attached to ring nitrogen atoms
    • C07D295/26—Sulfur atoms
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    • A61K31/495—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with two or more nitrogen atoms as the only ring heteroatoms, e.g. piperazine or tetrazines
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    • C07C311/22—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms
    • C07C311/29—Sulfonamides, the carbon skeleton of the acid part being further substituted by singly-bound oxygen atoms having the sulfur atom of at least one of the sulfonamide groups bound to a carbon atom of a six-membered aromatic ring
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    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D307/56—Heterocyclic compounds containing five-membered rings having one oxygen atom as the only ring hetero atom not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D309/08—Heterocyclic compounds containing six-membered rings having one oxygen atom as the only ring hetero atom, not condensed with other rings having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
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    • C07D333/04—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom
    • C07D333/06—Heterocyclic compounds containing five-membered rings having one sulfur atom as the only ring hetero atom not condensed with other rings not substituted on the ring sulphur atom with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to the ring carbon atoms
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    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/10—Spiro-condensed systems
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    • C07H—SUGARS; DERIVATIVES THEREOF; NUCLEOSIDES; NUCLEOTIDES; NUCLEIC ACIDS
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Definitions

  • This invention relates to sulfonamide derivatives useful as pharmaceuticals. More particularly, this invention relates to:
  • Lysosomal hydrolases of neutrophils have an important role in the defence reaction of organisms against tissue damage caused, for example, by microbes or inflammation.
  • Elastase and cathepsin G which are neutral serine proteinases existing locally in azurophil granules, play a part in the decomposition of connective tissue.
  • elastase degrades elastic connective tissue by cleaving the cross-linking of elastin which directly maintains the elasticity of e.g. lung tissue, by cleaving the hydrophobic part of protein [J. Cell. Biol., 40 , 366 (1969)] and selectively degrading the cross-linking of collagen as well as elastin [J. Biochem., 84 , 559 (1978)]. It also acts on tissue proteins such as proteoglycans [J. Clin. Invest., 57 , 615 (1976)]. It will be seen therefore that elastase plays an important role in the metabolism of connective tissue.
  • Elastase is inactivated by ⁇ 1 -proteinase inhibitor ( ⁇ 1 -PI) which is a common inhibitor for serine proteinases in vivo and an imbalance of enzyme and inhibitor causes the destruction of tissue [Schweiz. Med. Wshr., 114 , 895 (1984)].
  • ⁇ 1 -PI proteinase inhibitor
  • WO-A-93/11760 discloses a class of aromatic esters of phenylenedialkanoates as inhibitors of human neutrophil elastase.
  • EP-A-0539223 discloses a glycine derivative monosodium salt tetrahydrate having an inhibitory effect on elastase.
  • EP-A-0222608 discloses a class of derivatives of p-guanidinobenzoic acid which have an inhibitory effect on elastase.
  • the present invention provides a sulfonamide derivative of formula (I): wherein R 1 is pyrrolidinyl; R 2 and R 3 each, independently, is hydrogen atom or C1-4 alkyl; R 4 is C1-4 alkyl; m is an integer from 0 to 4; and in which R 5 and R 6 each, independently, is
  • the sulfonamide derivatives of the present invention are novel compared with compounds disclosed in the prior art.
  • the compounds of formula (A) described in EP-A-0347168 necessarily contain a pivaloyloxy group.
  • the compounds of the present invention have a phenyl ring which may be substituted by various substituents R 1 .
  • the compounds of formula (B) described in EP-A-0465802 include compounds in which R 4B represents S(O) pB R 9B .
  • R 9B can represent hydroxy, -ONa, optionally substituted C1-12 alkyl or optionally substituted cycloalkyl, but can not represent amino group.
  • the compounds of formula (C) described in EP-A-0484949 include those in which a substituent of Ar C represents S(O) pC R 9C .
  • R 9C can represent hydroxy, -ONa, optionally substituted C1-12 alkyl or optionally substituted cycloalkyl, but can not represent amino group.
  • the compounds of the present invention have a sulfonamide group which may be substituted by various substituents.
  • the compounds of the present invention have a chemical structure quite different from that of the compounds of formula (B) and (C).
  • related compounds show no activity by oral administration, but some compounds in the present invention have good stability, absorbability and solubility, and are, therefore, active as elastase inhibitors by oral administration.
  • C1-4 alkyl means methyl, ethyl, propyl, butyl and isomers thereof.
  • C1-8 alkyl means methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl and isomers thereof.
  • C1-8 alkylene represented by M means methylene, ethylene, trimethylene, tetramethylene, pentamethylene, hexamethylene, heptamethylene, octamethylene and isomers thereof.
  • phenyl C1-4 alkyl or phenyl C1-4 alkoxy means C 1-4 alkyl or C1-4 alkoxy substituted by a phenyl group.
  • phenyl C1-4 alkyl means methyl, ethyl, propyl, butyl and isomers thereof, which are substituted by a phenyl group.
  • phenyl C1-4 alkoxy means methoxy, ethoxy, propoxy, butoxy and isomers thereof, which are substituted by a phenyl group.
  • C2-5 acyl means acetyl, propionyl, butyryl, valeryl and isomers thereof.
  • C1-8 alkoxy means methoxy, ethoxy, propoxy, butoxy, pentyloxy, hexyloxy, heptyloxy, octyloxy and isomers thereof.
  • C1-4 alkoxy means methoxy, ethoxy, propoxy, butoxy and isomers thereof.
  • halogen atom means fluorine, chlorine, bromine and iodine.
  • examples of the 3-15 membered mono- or bi-cyclic aromatic heterocyclic ring, saturated heterocyclic ring or partly saturated heterocyclic ring containing one or two nitrogen atoms or one nitrogen atom and one sulfur atom or oxygen atom represented by that is, R 5 and R 6 , taken together with the nitrogen atom to which they are attached include pyrrole, imidazole, pyrazole, pyridine, pyrazine, pyrimidine, pyridazine, azepine, diazepine, aziridine, azetidine, pyrroline, pyrrolidine; imidazoline, imidazolidine, pyrazoline, pyrazolidine, piperidine, piperazine, tetrahydropyrimidine, hexahydropyrimidine, tetrahydropyridazine, hexahydropyridazine, hexahydroazepine, hexahydrodiaze
  • R 4 represents C 1-4 alkyl, for example methyl, ethyl or isopropyl. Methyl is especially preferred. When one or two substituents R 4 are present they preferably occupy one or both positions adjacent to the oxygen atom attached to the phenyl ring.
  • R 2 and R 3 preferably represents hydrogen, methyl, or ethyl, and the other represents methyl, ethyl, isopropyl, phenyl or trifluoromethyl.
  • the ethyl group represented by one of R 2 and R 3 is preferably in ⁇ -configuration.
  • R 1 is preferably on the 4-position of the phenyl ring. Pyrrolidin-1-yl is preferred as R 1 .
  • R 5 and R 6 when R 5 and R 6 , taken together with the nitrogen atom to which they are attched do not represent a heterocyclic ring, R 5 and R 6 preferably represent hydrogen; methyl; ethyl; propyl; methoxy; hydrogen is especially preferred.
  • the ring when R 5 and R 6 , taken together with the nitrogen atom to which they are attched represent a heterocyclic ring, the ring preferably represents pyrrolidine; indole; indoline; perhydroindole; benzoimidazole; morpholine; piperidine; piperazine; 7-azabicyclo[3.2.1]octane, 3-azabicyclo[3.2.2]nonane; tetrahydrooxazole; tetrahydrothiazole; Imidazole; hexahydrodiazepine; aziridine; azetidine; piperazine is especially preferred.
  • R 15 preferably represents amino; methoxy; dimethylamino; acetylamino; nitro; carboxy; ester, e.g. ethoxycarbonyl, t-butoxycarbonyl, 2-aminoethoxycarbonyl, 2-(2-hydroxyethoxy)ethoxycarbonyl, carboxy is especially preferred.
  • q preferably represents 0, 1 or 2, more preferably 0 or 1.
  • alkyl, alkylene and alkenylene groups include straight-chain and also branched-chain ones. Double bond in alkenylene includes E, Z and EZ mixture. Accordingly, all isomers produced by the existence of asymmetric carbon atoms are included in the present invention when groups such as branched-chain alkyl are present.
  • the compounds of the formula (I), of the present invention may be converted into the corresponding non-toxic salts or acid addition salts by methods known per se .
  • Suitable salts include salts of alkali metals (e.g. potassium or sodium), salts of alkaline earth metals (e.g. calcium or magnesium), ammonium salts, salts of pharmaceutically-acceptable organic amines (e.g. tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, piperidine, monoethanolamine, diethanolamine, tris(hydroxymethyl)amine, lysine, arginine or N-methyl-D-glucamine).
  • alkali metals e.g. potassium or sodium
  • salts of alkaline earth metals e.g. calcium or magnesium
  • ammonium salts salts of pharmaceutically-acceptable organic amines (e.g. tetramethylammonium, triethylamine, methylamine, dimethylamine, cyclopentylamine, benzylamine, phenethylamine, pipe
  • Suitable acid addition salts include the salts with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid, and the salts with organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid.
  • inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, phosphoric acid and nitric acid
  • organic acids such as acetic acid, trifluoroacetic acid, lactic acid, tartaric acid, oxalic acid, fumaric acid, maleic acid, benzenesulfonic acid, toluenesulfonic acid, isethionic acid, glucuronic acid and gluconic acid.
  • the compounds of the formula (I) or salts, of the present invention may be converted into the corresponding solvates by methods known per se.
  • Water-soluble solvates are preferred. Suitable solvates, for example, include the salts with water or with alcohol solvents such as ethanol.
  • Preferred compounds of the present invention are of the following formulae (I-A1), (I-A2), (I-B1) and (I-B2). (wherein all symbols are as hereinbefore defined).
  • Representative compounds of the present invention are illustrated by the compounds in the following Tables and the non-toxic salts and acid addition salts thereof.
  • Me is methyl
  • Et is ethyl
  • Pr is propyl
  • iPr is isopropyl
  • tBu is tert-butyl
  • the compounds of formula (I), of the present invention may be prepared by esterifying a compound of formula (II) wherein R 1a is pyrrolidinyl; and R 2 and R 3 are as defined in claim 1, with a compound of formula (III) wherein R 4 and m are as defined in claim 1, (in which R 5a and R 6a each, independently, is
  • Protected hydroxy means, for example, hydroxy protected by a protecting group which is removable under acid conditions (e.g. C2-4 alkoxyalkyl, t-butyldimethylsilyl, tetrahydropyran (THP), triphenylmethyl) or hydroxy protected by a protecting group which is removable by hydrogenation (e.g. benzyl).
  • a protecting group which is removable under acid conditions e.g. C2-4 alkoxyalkyl, t-butyldimethylsilyl, tetrahydropyran (THP), triphenylmethyl
  • hydroxy protected by a protecting group which is removable by hydrogenation e.g. benzyl
  • Hydroxy protected by a protecting group which is removable under acid conditions means, for example, hydroxy group protected by C2-4 alkoxyalkyl, t-butyldimethylsilyl, tetrahydropyran (THP) or triphenylmethyl.
  • Protected amino acid, ⁇ -amino acid or piperazino ring means, for example, amino acid, ⁇ -amino acid or piperazino ring protected by t-butoxycarbonyl (Boc) or benzyloxycarbonyl (Cbz).
  • -CHO protected by a protecting group which is removable under acid conditions means, for example, -CHO protected by acetal (e.g. dimethylacetal or diethylacetal or ketal (e.g. ethylenedioxyketal or trimethylenedioxyketal).
  • acetal e.g. dimethylacetal or diethylacetal or ketal (e.g. ethylenedioxyketal or trimethylenedioxyketal).
  • the reactions (1), (2) and (3) hereinbefore described may be preferably carried out in an atmosphere of inert gas (e.g. argon or nitrogen) under anhydrous conditions.
  • inert gas e.g. argon or nitrogen
  • the hydrolysis of t-butylester group or the reaction resulting from treatment with acid is known per se and may be carried out, for example, by using an organic acid (e.g. trifluoroacetic acid) or an inorganic acid (e.g. hydrochloric acid), or a mixture thereof, in an inert organic solvent (e.g. methylene chloride, chloroform, methanol, dioxane, ethyl acetate or anisole) at a temperature of from 0°C to 90°C.
  • an organic acid e.g. trifluoroacetic acid
  • an inorganic acid e.g. hydrochloric acid
  • an inert organic solvent e.g. methylene chloride, chloroform, methanol, dioxane, ethyl acetate or anisole
  • the hydrogenolysis is known per se , and may be carried out, for example, in an inert solvent [such as an ether (e.g., tetrahydrofuran, dioxane, diethoxyethane or diethyl ether), an alcohol (e.g., methanol or ethanol), a benzene analogue (e.g. benzene or toluene), a ketone (e.g. acetone or methyl ethyl ketone), a nitrile (e.g.
  • an inert solvent such as an ether (e.g., tetrahydrofuran, dioxane, diethoxyethane or diethyl ether), an alcohol (e.g., methanol or ethanol), a benzene analogue (e.g. benzene or toluene), a ketone (e.g. acetone or methyl ethyl ketone),
  • acetonitrile an amine (e.g., dimethylformamide), water, ethyl acetate, acetic acid or a mixture of two or more of them], in the presence of a hydrogenation catalyst (e.g., palladium on activated carbon, palladium black, palladium, palladium hydroxide on carbon, platinum oxide, nickel or Raney nickel (registered trade mark)), in the presence or absence of an inorganic acid (e.g.
  • a hydrogenation catalyst e.g., palladium on activated carbon, palladium black, palladium, palladium hydroxide on carbon, platinum oxide, nickel or Raney nickel (registered trade mark)
  • an inorganic acid e.g.
  • hydrochloric acid sulfuric acid, hypochlorous acid, boric acid or tetrafluoroboric acid
  • organic acid e.g., acetic acid, p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid or formic acid
  • acetic acid p-toluenesulfonic acid, oxalic acid, trifluoroacetic acid or formic acid
  • an acid its salt may be used at the same time.
  • the sulfuric acid esterification is known per se, and may be carried out, for example, by reacting sulfur trioxide pyridine complex in the presence of a tertiary amine (e.g. pyridine) at a temperature of from 0°C to 40°C.
  • a tertiary amine e.g. pyridine
  • the compounds of formulae (II) and (III) used as starting materials may be prepared by the methods of the following Scheme 1 or by methods known per se or are commercially available compounds.
  • 2-phenylbutanoic acid is commercially available.
  • the compounds may also be prepared by the methods described in the Examples of the present specification.
  • DMSO dimethylsulfoxide
  • HSE human polymorphonuclear elastase
  • a test compound suspended in 0.5 % Carboxymethylcellulose or 80 % Polyethyleneglycol, 400 or 2 % Tween 80 was administered orally to a group of 5 Syrian hamsters.
  • 10 U/0.1 ml of HSE was injected intratracheally via surgically exposed trachea under pentobarbital anesthesia (60 mg/kg, i.p.) to induce lung injury.
  • hamsters were bled to sacrifice and subjected to bronchoalveolar lavage with 2.5 ml of saline and recovered lavage solution (BALF).
  • the recovered BALF (0.5 ml) was diluted by 4 times with 2 % aqueous solution sodium carbonate and sonicated for 10 sec.
  • the lavage fluid was further diluted by 2.5 times with 2% aqueous solution sodium carbonate and the amount of blood in BALF was calculated from absorbance at 414 nM using standard curve.
  • Example No. inhibition at 500 mg/kg (%) 1(68) 51 Comp. 1(90) 65 Inv. 2 81 Inv. 2(42) 67 Inv. 2(69) 83
  • Example No. ED 50 1 (139) 192 mg/kg 2(274) 132 mg/kg 2(276) 73 mg/kg
  • the toxicity of the compounds of the present invention is very low. Therefore, the compounds of the present invention may be considered to be sufficiently safe and suitable for pharmaceutical use.
  • chronic obstructive pulmonary disease such as emphysema, rheumatoid arthritis, atherosclerosis, adult respiratory distress syndrome (ARDS), glomerular nephritis, myocardial infarction, idiopathic
  • the compounds of the formula (I), of the present invention, or non-toxic salts, acid addition salts or solvates thereof may normally be administered systemically or locally usually by oral or parenteral administration.
  • the doses to be administered are determined depending upon, for example, age, body weight, symptom, the desired therapeutic effect, the route of administration, and the duration of the treatment.
  • the doses per person are generally from 1 mg to 1000 mg, by oral administration, up to several times per day, or from 0.1 mg to 100 mg, by parenteral administration up to several times per day, or by continuous administration for from 1 to 24 hrs. per day from vein.
  • the doses to be used depend upon various conditions. Therefore, there are cases in which doses lower than or greater than the ranges specified above may be used.
  • the compounds of the present invention may be administered in the form of, for example, solid compositions, liquid compositions or other compositions for oral administration, injections, liniments or suppositories for parenteral administration.
  • Solid compositions for oral administration include compressed tablets, pills, capsules, dispersible powders, and granules.
  • Capsules include hard capsules and soft capsules.
  • one or more of the active compound(s) may be admixed with at least one inert diluent (such as lactose, mannitol, glucose, hydroxypropyl cellulose, microcrystalline cellulose, starch, polyvinylpyrrolidone or magnesium metasilicate aluminate).
  • the compositions may also comprise, as is normal practice, additional substances other than inert diluents: e.g. lubricating agents (such as magnesium stearate), disintegrating agents (such as cellulose calcium glycolate), stabilizing agents (such as lactose), and agents to assist dissolution (such as glutamic acid or asparaginic acid).
  • the tablets or pills may, if desired, be coated with a film of gastric or enteric material (such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate), or be coated with two or more films. And further, coating may include containment within capsules of absorbable materials such as gelatin.
  • a film of gastric or enteric material such as sugar, gelatin, hydroxypropyl cellulose or hydroxypropylmethyl cellulose phthalate
  • coating may include containment within capsules of absorbable materials such as gelatin.
  • Liquid compositions for oral administration include pharmaceutically-acceptable solutions, emulsions, suspensions, syrups and elixirs.
  • inert diluent(s) commonly used in the art (e.g. purified water or ethanol).
  • inert diluents commonly used in the art
  • such compositions may also comprise adjuvants (such as wetting agents or suspending agents, sweetening agents, flavouring agents, perfuming agents, and preserving agents.
  • compositions for oral administration include spray compositions which may be prepared by known methods and which comprise one or more of the active compound(s).
  • Spray compositions may comprise additional substances other than inert diluents: e.g. stabilizing agents (such as sodium sulfate), isotonic buffers (such as sodium chloride, sodium citrate or citric acid).
  • stabilizing agents such as sodium sulfate
  • isotonic buffers such as sodium chloride, sodium citrate or citric acid
  • Injections for parenteral administration include sterile aqueous or non aqueous solutions, suspensions and emulsions.
  • one or more active compound(s) may be admixed with at least one inert aqueous diluent(s) (e.g. distilled water for injection or physiological salt solution) or inert non-aqueous diluent(s) (e.g. propylene glycol, polyethylene glycol, olive oil, ethanol or POLYSORBATE80 (registered trade mark).
  • inert aqueous diluent(s) e.g. distilled water for injection or physiological salt solution
  • inert non-aqueous diluent(s) e.g. propylene glycol, polyethylene glycol, olive oil, ethanol or POLYSORBATE80 (registered trade mark).
  • Injections may comprise additional ingredients other than inert diluents: e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (e.g. lactose), assisting agents such as agents to assist dissolution (e.g. glutamic acid or asparaginic acid).
  • additional ingredients e.g. preserving agents, wetting agents, emulsifying agents, dispersing agents, stabilizing agents (e.g. lactose), assisting agents such as agents to assist dissolution (e.g. glutamic acid or asparaginic acid).
  • They may be sterilized for example, by filtration through a bacteria-retaining filter, by incorporation of sterilizing agents in the compositions or by irradiation. They may also be manufactured in the form of sterile solid compositions, for example, by freeze-drying, which may be dissolved in sterile water or some other sterile diluent(s) for injection immediately before used.
  • compositions for parenteral administration include liquids for external use, and endermic liniments, ointment, suppositories and pessaries which comprise one or more of the active compound(s) and may be prepared by methods known per se.
  • the solvents in parentheses show the developing or eluting solvents and the ratios of the solvents used are by volume in chromatographic separations and TLC.
  • the NMR data show the solvents used in the measurements in parentheses.

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Claims (9)

  1. Composé de formule (I)
    Figure 02040001
    dans lequel R1 est un pyrrolidinyle ;
       R2 et R3 indépendamment l'un de l'autre, sont un atome d'hydrogène ou un alkyle en C1 à C4 ;
       R4 est un alkyle en C1 à C4 ;
       m est un nombre entier compris entre 0 et 4 ; et
    Figure 02040002
       dans lequel R5 et R6 indépendamment l'un de l'autre, sont
    1) un atome d'hydrogène,
    2) un hydroxy,
    3) un alkyle en C1 à C8,
    4) un alkoxy en C1 à C8,
    5) -M-R16
       (dans lequel M est une liaison simple ou un alcoylène en C1 à C8), et
       R16 est
       un cycle hétérocyclique aromatique mono- ou bi-cyclique de 5 à 15 chaínons, un cycle hétérocyclique saturé ou un cycle hétérocyclique partiellement saturé contenant de un à quatre atomes d'azote, un ou deux atomes d'oxygène ou un atome d'azote et un atome de soufre ou un atome d'oxygène, non substitué ou substitué par 1 à 4 substituants choisis dans le groupe comprenant un alkyle en C1 à C4, un alkoxy en C1 à C4, un hydroxy, un phényl(alkyle en C1 à C4), -COOR26 (dans lequel R26 est un atome d'hydrogène, un alkyle en C1 à C8, un phényle ou un phényl(alkyle en C1 à C4), un hydroxy(alkyle en C1 à C4) ou un alkoxyalkyle en C2 à C4),
    6) -J-COOR29, dans lequel R29 est un atome d'hydrogène, et
       J est
    Figure 02050001
       (dans lequel
       R30 et R31 indépendamment l'un de l'autre, est un atome d'hydrogène ou un alkyle en C1 à C8 ; ou
    Figure 02050002
       dans lequel R5 et R6, pris ensemble avec l'atome d'azote auquel ils sont liés représentent un cycle hétérocyclique aromatique mono- ou bi-cyclique de 3 à 15 chaínons, un cycle hétérocyclique saturé ou un cycle hétérocyclique partiellement saturé contenant un ou deux atomes d'azote ou un atome d'azote et un atome de soufre ou un atome d'oxygène,
       q est un nombre entier compris entre 0 et 4, et
       R15 est
    1) un alkyle en C1 à C4,
    2) un alkoxy en C1 à C4,
    3) un phényl(alkoxy en C1 à C4),
    4) un nitro,
    5) -COOR36 (dans lequel R36 est un atome d'hydrogène, ou un alkyle en C1 à C4 substitué par -NR39R40 (dans lequel R39 et R40 indépendamment l'un de l'autre, sont un atome d'hydrogène ou un alkyle en C1 à C4),
    6) -NR43R44 (dans lequel R43 et R44 indépendamment l'un de l'autre, est un atome d'hydrogène, un alkyle en C1 à C4 ou un acyle en C2 à C5),
    7) -CONR45R46 (dans lequel R45 et R46 indépendamment l'un de l'autre, est un atome d'hydrogène ou un alkyle en C1 à C4 substitué par un hydroxy),
    8) un alkyle en C1 à C4 substitué par -OSO3H ;
    ou un sel non toxique, un sel d'addition à un acide ou un solvat de celui-ci.
  2. Composé selon la revendication 1, dans lequel
    Figure 02060001
       dans lequel tous les symboles sont tels que définis dans la revendication 1.
  3. Composé selon la revendication 1, dans lequel
    Figure 02060002
       dans lequel tous les symboles sont tels que définis dans la revendication 1.
  4. Composé selon la revendication 1, lequel est
       21) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(N-méthyl-N-méthoxysulfamoyl)-2-méthylphényle,
       35) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-[N-(quinuclidin-3-yl)sulfamoyl]-2-méthylphényle,
       36) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-[N-2-(morpholin-4-yl)éthylsulfamoyl]-2-méthylphényle,
       38) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-[N-(pipéridin-4-yl)sulfamoyl]-2-méthylphényle,
       56) le (2S)-2-[4'-(pyrrolidin-1"-yl)phényl]butanoate de 4-[2-(morpholin-4-yl)éthylaminosulfonyl]-2-méthyl phényle,
       57) le (2S)-2-[4'-(pyrrolidin-1"-yl)phényl]butanoate de 4-(quinuclidin-3-ylaminosulfonyl)-2-méthylphényle,
       101) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-[N-(1,1-diméthyl-1-carboxyméthyl)-N-propylaminosulfonyl] - 2-méthylphényle,
       103) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(N-hydroxyaminosulfonyl)-2-méthylphényle,
       ou un sel non toxique, un sel d'addition à un acide ou un solvat de celui-ci.
  5. Composé selon la revendication 1, lequel est
       11) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(6-nitroindolin-1-ylsulfonyl)-2-méthylphényle,
       14) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(7-aminoindolin-1-ylsulfonyl)-2-méthylphényle,
       15) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(benzimidazol-1-ylsulfonyl)-2-méthylphényle,
       31) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(morpholin-4-ylsulfonyl)-2-méthylphényle,
       33) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(pipérazin-4-ylsulfonyl)-2-méthylphényle,
       40) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(4-méthylpipérazin-1-ylsulfonyl)-2-méthylphényle,
       41) le (2R)-2-[4'-(pyrrolidin-1"-yl)phényl]butanoate de 4-(5-nitroindolin-1-ylsulfonyl)-2-méthylphényle,
       44) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S)-4-(2'-carboxypyrrolidin-1'-ylsulfonyl)-2-méthyl phényle,
       48) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S,4'R)-4-(2'-carboxy-4'-benzyloxypyrrolidin-1'-yl sulfonyl)phényle,
       56) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(2-carboxyindolin-1-ylsulfonyl)phényle,
       66) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-[2-(N-hydroxyéthylcarbamoyl)indolin-1-ylsulfonyl]-2-méthylphényle,
       67) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(2-carboxy-5,6-diméthoxyindol-1-ylsulfonyl)-2-méthyl phényle,
       68) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-[2-(2-aminoéthyl)oxycarbonylindolin-1-ylsulfonyl]-2-méthylphényle,
       69) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(2-carboxyindol-1-ylsulfonyl)-2-méthylphényle,
       89) le (2S)-2-[4'-(pyrrolidin-1"-yl)phényl]butanoate de (2'R)-4-(2'-carboxypyrrolidin-1'-ylsulfonyl)-2-méthyl phényle,
       90) le (2R)-2-[4'-(pyrrolidin-1"-yl)phényl]butanoate de (2'S)-4-(2'-carboxypyrrolidin-1'-ylsulfonyl)-2-méthyl phényle,
       95) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(2-carboxypipéridin-1-ylsulfonyl)-2-méthylphényle,
       98) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S,4'R)-4-(2'-carboxy-4'-méthoxypyrrolidin-1'-yl sulfonyl)-2-méthylphényle,
       99) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'R,4'R)-4-(2'-carboxy-4'-méthoxypyrrolidin-1'-yl sulfonyl)-2-méthylphényle,
       104) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S)-4-(2'-carboxypyrrolidin-1'-ylsulfonyl)-2-éthyl phényle,
       107) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S,4'S)-4-(2'-carboxy-4'-acétylaminopyrrolidin-1'-yl sulfonyl)-2-méthylphényle,
       109) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S,4'R)-4-(2'-carboxy-4'-acétylaminopyrrolidin-1'-yl sulfonyl)-2-méthylphényle,
       113) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S, 6'S)-4-(2',6'-diméthylpipérazin-4'-ylsulfonyl)-2-méthyl phényle,
       114) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de 4-(2-méthylpipérazin-4-ylsulfonyl)-2-méthylphényle,
       115) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S,4'R)-4-[2'-carboxy-4'-(N,N-diméthylamino) pyrrolidin-1'-ylsulfonyl]-2-méthylphényle,
       116) le 2-[4-(pyrrolidin-1-yl)phényl]butanoate de (2'S,4'R)-4-(2'-carboxy-4'-méthylaminopyrrolidin-1'-ylsulfonyl)-2-méthylphényle,
       117) le (2S)-2-[4'-(pyrrolidin-1"-yl)phényl] butanoate de 4-(pipérazin-4-ylsulfonyl)-2-éthylphényle,
       125) le (2S)-2-[4'-(pyrrolidin-1"-yl)phényl] butanoate de 4-(2-méthylpipérazin-4-ylsulfonyl)-2-méthylphényle,
       128) le 2-[4-(pyrrolidin-1-yl)phényl)butanoate de (2'S)-4-(2'-hydroxysulfonyloxyméthylpyrrolidin-1'-yl sulfonyl)-2-méthylphényle,
       ou un sel non toxique, un sel d'addition à un acide ou un solvat de celui-ci.
  6. Composition pharmaceutique qui comprend, en tant que substance active, une quantité efficace d'un composé de formule (I) tel que défini dans la revendication 1, un sel non toxique de celui-ci, un sel d'addition à un acide de celui-ci ou un solvat de celui-ci, avec un vecteur ou enrobée.
  7. Composé de formule (I) tel que défini dans la revendication 1 ou un sel non toxique de celui-ci ou un sel non toxique d'addition à un acide de celui-ci ou un solvat de celui-ci pour l'utilisation dans la fabrication de composition pharmaceutique comme inhibiteur d'élastase.
  8. Composé de formule (I) tel que défini dans la revendication 1 ou un sel non toxique de celui-ci ou un sel non toxique d'addition de celui-ci ou un solvat de celui-ci pour l'utilisation dans la fabrication de composition pharmaceutique pour la prévention et/ou le traitement de maladies induites par une augmentation anormale de la dégradation d'élastine, de fibres de collagène et/ou de protéoglycane, résultant de l'action de l'élastase sur un animal mammifère, particulièrement un humain (par exemple, la maladie pulmonaire obstructive chronique telle que l'emphysème, la polyarthrite rhumatoïde, l'athérosclérose, le syndrome de détresse respiratoire de l'adulte (SDRA), la glomérulonéphrite, l'infarctus du myocarde, la recto-colite hémorragique ou la gingivite).
  9. Procédé pour la préparation d'un composé de formule (I) tel que défini dans la revendication 1 ledit procédé comprenant l'estérification d'un composé de formule :
    Figure 02110001
       dans lequel R1a est un pyrrolidinyle ;
       et R2 et R3 sont tels que définis dans la revendication 1,
       avec un composé de formule (III)
    Figure 02110002
       dans lequel R4 et m sont tels que définis dans la revendication 1,
    Figure 02110003
       (dans lequel R5a et R6a indépendamment l'un de l'autre, est
    1) un atome d'hydrogène (à la condition que, R5a et R6a ne représentent pas un atome d'hydrogène en même temps),
    2) un hydroxy,
    3) un hydroxy protégé par un groupe protecteur qui est labile en conditions acides,
    4) un t-butoxycarbonyle,
    5) un benzyloxycarbonyle,
    6) un alkyle en C1 à C8,
    7) un alkoxy en C1 à C8,
    8) -M-R16a (dans lequel M est tel que défini dans la revendication 1, et R16a est un cycle hétérocyclique aromatique mono- ou bi-cyclique de 5 à 15 chaínons, un cycle hétérocyclique saturé ou un cycle hétérocyclique partiellement saturé contenant un à quatre atomes d'azote, un ou deux atomes d'oxygène ou un atome d'azote et un atome de soufre ou un atome d'oxygène, non substitué ou substitué par 1 à 4 substituants choisis dans le groupe comprenant un alkyle en C1 à C4, un alkoxy en C1 à C4, un hydroxy, un phényl(alkyle en C1 à C4), -COOR26 (dans lequel R26 est tel que défini dans la revendication 1), un hydroxy(alkyle en C1 à C4) dans lequel l'hydroxy est protégé par un groupe protecteur qui est labile en conditions acides ou un alkoxyalkyle en C2 à C4),
    9) -Ja-COOR29 (dans lequel R29 est tel que défini dans la revendication 1,
       Ja est
    Figure 02120001
       (dans lequel
       R30a et R31a indépendamment l'un de l'autre, est i) un atome d'hydrogène ou, ii) un alkyle en C1 à C8, ou
    Figure 02130001
       dans lequel R5a et R6a, pris ensemble avec l'atome d'azote auquel ils sont liés représentent un cycle hétérocyclique aromatique mono- ou bi-cyclique de 3 à 15 chaínons, un cycle hétérocyclique saturé ou un cycle hétérocyclique partiellement saturé contenant un ou deux atomes d'azote ou un atome d'azote et un atome de soufre ou un atome d'oxygène,
       q est tel que défini dans la revendication 1,
       R15a est
    1) un alkyle en C1 à C4,
    2) un alkoxy en C1 à C4,
    3) un phényl(alkoxy en C1 à C4),
    4) un nitro,
    5) -COOR36a (dans lequel R36a est un atome d'hydrogène, un alkyle en C1 à C4 substitué par -NR39aR40a (dans lequel R39a et R40a indépendamment l'un de l'autre, est un atome d' hydrogène (à la condition que, R39a et R40a ne représentent pas un atome d'hydrogène en même temps, un t-butoxycarbonyle, un benzyloxycarbonyle ou un alkyle en C1 à C4),
    6) -NR43aR44a (dans lequel R43a et R44a indépendamment l'un de l'autre, est un atome d'hydrogène (à la condition que, R43a et R44a ne représentent pas un atome d'hydrogène en même temps), un t-butoxycarbonyle, un benzyloxycarbonyle, un alkyle en C1 à C4 ou un acyle en C2 à C5,
    7) -CONR45aR46a (dans lequel R45a et R46a indépendamment l'un de l'autre, sont un atome d'hydrogène, ou un alkyle en C1 à C4 substitué par un hydroxy ou un hydroxy protégé),
       ou
       peut être préparé en estérifiant un composé de formule (II) avec un composé de formule (III) pour obtenir un composé ayant un ou plusieurs groupes protégés, puis ensuite en éliminant les groupes protecteurs,
       ou peut être préparé en estérifiant un composé de formule (II) avec un composé de formule (III), au besoin, en éliminant les groupes protecteurs pour obtenir un composé ayant R15 représentant un alkyle (en C1 à C4) substitué par un hydroxy, puis ensuite en soumettant à une estérification avec de l'acide sulfurique et facultativement en convertissant un composé de formule (I) ainsi obtenu en un sel non toxique, un sel d'addition à un acide ou un solvat de celui-ci.
EP96307048A 1995-09-27 1996-09-27 Dérivés sulfonamide ayant une activité inhibitrice vis-à-vis de l'élastase humaine Expired - Lifetime EP0769498B9 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7781481B2 (en) 2005-12-22 2010-08-24 Novartis Ag N-arylsulfonyl-2,3-dihydro-1H-indoles and the use thereof as CCR9 inhibitors
CN116411028A (zh) * 2023-01-06 2023-07-11 西南大学 桔小实蝇嗅觉受体OR43a-1和OR63a-2的应用及其突变体的构建方法

Families Citing this family (20)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
KR980009238A (ko) 1995-07-28 1998-04-30 우에노 도시오 설포닐아미노산 유도체
RU2221782C2 (ru) 1996-08-28 2004-01-20 Дзе Проктер Энд Гэмбл Компани Замещенные циклические аминовые ингибиторы металлопротеаз
US6872742B2 (en) 1996-08-28 2005-03-29 The Procter & Gamble Company Substituted cyclic amine metalloprotease inhibitors
DE19742263A1 (de) * 1997-09-25 1999-04-01 Asta Medica Ag Neue spezifische Immunophilin-Liganden als Antiasthmatika, Antiallergika, Antirheumatika, Immunsuppressiva, Antipsoriatika, Neuroprotektiva
WO1999062880A1 (fr) 1998-06-03 1999-12-09 Gpi Nil Holdings, Inc. Sulfonamides a liaison n d'acides carboxyliques n-heterocycliques ou d'isosteres d'acide carboxylique
IL140041A0 (en) * 1998-06-03 2002-02-10 Guilford Pharm Inc Multiple heteroatom containing heterocyclic ring compounds substituted with carboxylic acids and isosteres thereof
US6251932B1 (en) 1998-09-25 2001-06-26 Asta Medica Ag Immunophilin ligands
CZ20013176A3 (cs) 1999-03-03 2002-04-17 The Procter & Gamble Company Sloučenina vytvářející inhibitor metaloproteinasy, farmaceutický prostředek, způsob přípravy léčiva a léčivo
EP1214301A1 (fr) 1999-08-27 2002-06-19 Eli Lilly And Company Composes n,n-arylsulfonylglycine hypoglycemiques
TW200303742A (en) * 2001-11-21 2003-09-16 Novartis Ag Organic compounds
DE10229777A1 (de) * 2002-07-03 2004-01-29 Bayer Ag Indolin-Phenylsulfonamid-Derivate
DE10300015A1 (de) * 2003-01-03 2004-07-15 Aventis Pharma Deutschland Gmbh Iminosäurederivate als Inhibitoren von Matrix-Metallproteinasen
DE10335449A1 (de) * 2003-08-02 2005-02-17 Bayer Healthcare Ag Bicyclische Indolinsulfonamid-Derivate
US7622491B2 (en) * 2004-08-13 2009-11-24 Metabolex Inc. Modulators of PPAR and methods of their preparation
CA2632670A1 (fr) * 2005-08-19 2007-02-22 Elan Pharmaceuticals, Inc. Inhibiteurs sulfonamides n-cycliques pontes de la gamma secretase
US7838550B2 (en) * 2006-02-17 2010-11-23 Wyeth Llc Selective N-sulfonylation of 2-amino fluoro- and trifluoroalkyl substituted alcohols
US7687666B2 (en) * 2006-02-17 2010-03-30 Wyeth Methods for preparing sulfonamide substituted alcohols and intermediates thereof
BRPI0716897A2 (pt) 2006-09-21 2013-10-22 Activx Biosciences Inc Composto ou um derivado farmaceuticamente aceitável do mesmo, composição farmacêutica, métodos para inibir uma ação de uma serina hidrolase e para tratamento de uma doença mediada por serina hidrolase, e, artigo de fabricação.
TW201639811A (zh) 2015-03-13 2016-11-16 佛瑪治療公司 作為ＨＤＡＣ８抑制劑之α－桂皮醯胺化合物與組成物
GB202108544D0 (en) * 2021-06-15 2021-07-28 Z Factor Ltd Compounds and their use for the treatment of alpha1-antitrypsin deficiency

Family Cites Families (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
ATE67180T1 (de) * 1985-11-12 1991-09-15 Ono Pharmaceutical Co P-guanidinbenzoesaeurederivate und pharmazeutische mittel, die sie als aktiven inhaltsstoff enthalten.
CA1340191C (fr) * 1988-06-13 1998-12-15 Katsuhiro Imaki Derives d'ester phenylique de l'acide pivalique, avec substitution en p
US5214191A (en) * 1990-05-22 1993-05-25 Cortech, Inc. Oxidant sensitive and insensitive aromatic esters as inhibitors of human neutrophil elastase
ZA918719B (en) * 1990-11-07 1992-08-26 Cortech Inc Ester inhibitors
US5240956A (en) * 1990-11-07 1993-08-31 Cortech, Inc. Ester inhibitors
EP0539223A1 (fr) * 1991-10-25 1993-04-28 Ono Pharmaceutical Co., Ltd. Tétrahydrate d'un sel monosodique d'un dérivé de glycine ayant un effet inhibiteur sur l'élastase
US5216022A (en) * 1991-12-19 1993-06-01 Cortech, Inc. Aromatic esters of phenylenedialkanoates as inhibitors of human neutrophil elastase

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US7781481B2 (en) 2005-12-22 2010-08-24 Novartis Ag N-arylsulfonyl-2,3-dihydro-1H-indoles and the use thereof as CCR9 inhibitors
CN116411028A (zh) * 2023-01-06 2023-07-11 西南大学 桔小实蝇嗅觉受体OR43a-1和OR63a-2的应用及其突变体的构建方法

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KR100266467B1 (ko) 2000-10-02
AU6583796A (en) 1997-04-10
US5795890A (en) 1998-08-18
US5998410A (en) 1999-12-07
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HUP9602635A3 (en) 1998-12-28
HUP9602635A2 (en) 1997-11-28
CA2186665A1 (fr) 1997-03-28
NO964045L (no) 1997-04-01
EP0769498A1 (fr) 1997-04-23
NO307251B1 (no) 2000-03-06
NO964045D0 (no) 1996-09-26
ATE261960T1 (de) 2004-04-15
HU9602635D0 (en) 1996-11-28

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